System, method, and probe for monitoring pH levels of a sample medium

ABSTRACT

A system for monitoring a pH level of a sample medium is disclosed herein as including a pH probe having a pH-sensitive electrode, a reference electrode and a temperature electrode arranged within a housing of the pH probe. The probe housing generally includes a flexible inner tube and a flexible outer tube, the inner tube being concentrically arranged within the outer tube. Preferably, a size of the probe housing minimizes the amount of trauma introduced by insertion of the pH probe into physiological tissues, muscles or fluids. The system also includes a processing means, which is coupled to the pH probe for determining the pH of the sample medium. A method of forming a pH-sensitive electrode, a method of manufacturing a pH probe, and a method for using a pH probe are also disclosed herein.

CONTINUING DATA

The present application is a divisional application from priorapplication Ser. No. 11/669,289 filed Jan. 31, 2007 now U.S. Pat. No.7,972,495 which is a divisional from application Ser. No. 10/431,132filed May 7, 2003 now U.S. Pat. No. 7,182,847.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a system, method and probe for use inmeasuring hydrogen ion concentrations, or pH, in a sample medium and,more particularly, to a minimally invasive, micro-sized pH probe havinga pH-sensitive electrode, a reference electrode and a temperatureelectrode arranged within a probe housing. Preferably, a size of theprobe housing minimizes the amount of trauma introduced by insertion ofthe pH probe into physiological tissues, muscles, or fluids.

2. Description of the Related Art

The following descriptions and examples are not admitted to be prior artby virtue of their inclusion within this section.

Generally speaking, pH is a measure of the hydrogen ion (H⁺)concentration within an aqueous solution. More specifically, pH is anindication of the acidity or alkalinity of a solution, and is defined asthe negative logarithm of the H⁺ concentration. A solution having a pHvalue of 7.0 is typically considered a neutral solution, whereas lowerpH values (i.e., higher H⁺ concentrations) indicate acidic solutions andhigher pH values (i.e., lower H⁺ concentrations) indicate basic oralkaline solutions. In this manner, the acidity or alkalinity of asolution may be measured on a pH scale of about −2 to about 16. For eachpH unit above 7.0, the H⁺ concentration is decreased tenfold, and viceversa.

In physiological solutions, maintenance of proper pH levels is critical,due to the pH dependency of chemical reactions that occur in the body.For example, all cells in the body continually exchange chemicals (e.g.,nutrients, waste products, and ions) with interstitial fluids, which inturn, exchange chemicals with plasma in the bloodstream. A dominant modeof exchange between these fluids (i.e., intracellular fluid,interstitial fluid, and blood plasma) is diffusion through membranechannels, due to a concentration gradient associated with the chemicalcomposition (and thus the pH) of these fluids. In order to maintainproper pH levels inside the cells, pH levels outside the cells must bekept relatively constant. This constancy is known in biology as H⁺homeostasis.

Cellular health begins to decline when H⁺ homeostasis between theintracellular fluid, interstitial fluid and blood plasma is notmaintained. As an example, the normal pH of (arterial) blood plasma,otherwise referred to as “physiological pH,” is about 7.4. If, forinstance, pH levels of the blood plasma and interstitial fluid are toolow (i.e., less than about 7.35), an excess of hydrogen ions will enterthe cell, thereby increasing the acidity of the intracellular fluid andcreating a condition called “acidosis.” Examples of conditions thatcause physiological pH to drop may include hypoxia due to, for example,hypoventilation (e.g., caused by lung and airway disorders), low cardiacoutput (e.g., during shock states and myocardial infarction), and blooddefects (e.g., sepsis, anemia and CO poisoning); inhalation or increasedproduction of CO₂; and accumulation of organic or inorganic acids (e.g.,lactic acid, hydrochloric acid and carbonic acid). Extreme acidosisoccurs in the cells when physiological pH drops to approximately 7.0.

If, on the other hand, pH levels of the blood plasma and interstitialfluid are too high (i.e., greater than about 7.45), an excess ofhydrogen ions will leave the cell, thereby increasing the alkalinity ofthe intracellular fluid and creating a condition called “alkalosis.”Examples of conditions that cause physiological pH to rise may includehyperventilation, fever, some types of central nervous system damage,and loss of potassium (K⁺), sodium (Na⁺) and hydrochloric acid (HCl) dueto pyloric obstruction, prolonged vomiting or diuretic alkalosis.Extreme alkalosis occurs in the cells when physiological pH increases toapproximately 7.7.

As such, monitoring blood plasma pH may provide some indication of theseverity of certain illnesses or medical conditions. Conventionalelectrodes used for monitoring intra-arterial or intra-venous bloodplasma pH generally include glass or antimony electrodes. A typicalglass electrode consists of a glass bulb, which encloses a metalelectrode immersed within an electrolytic solution. Unfortunately,conventional glass electrodes suffer from many disadvantages. Forexample, glass electrodes are often extremely fragile, and therefore,undesirably expensive to produce and transport. Due to their relativelyhigh electrical impedance, glass electrodes also demonstrate a prolongedtime response and require heavily shielded probe leads to reduceunwanted noise components in the probe signal. In addition, the inherentrigidity of glass electrodes does not allow for minimization of patientdiscomfort when measuring in vivo pH levels.

As yet another disadvantage, most glass electrodes require the use of anexternal reference electrode, which as described below, is undesirablefor several reasons. Recently, combination pH and reference electrodeshave been fabricated within a single glass enclosure. However, thepresent inventors are unaware of a commercially available combination pHand reference glass electrode having a size substantially less than 1.0mm in diameter.

In an effort to overcome the disadvantages of glass electrodes, antimonyelectrodes have been constructed for use in monitoring in vitro and invivo pH levels. As one advantage, antimony electrodes can be made muchsmaller and more robust than pH electrodes made from glass. In addition,the antimony electrode is a relatively low impedance device (e.g., 1 MΩor less) compared to the glass electrode (e.g., 12 MΩ). As such,antimony electrodes demonstrate shorter time responses than glasselectrodes and do not require shielding, in most cases.

However, conventional antimony electrodes suffer from their owndisadvantages. In one example, a method of constructing an antimonyelectrode includes forming an antimony rod from which relatively smallfragments are cut or otherwise detached from the rod. After attachingone of the fragments to a wire lead, the assembly is encased within aglass tube leaving an upper portion of the antimony fragment exposed forsensing purposes. Unfortunately, antimony electrodes formed in such amanner suffer from the effects of a rough sensing surface; namely,undesirable fluctuations in pH measurements.

In an effort to reduce signal fluctuations, another method has beendisclosed in which an antimony fragment and attached wire lead arecompletely coated in a hard-setting acrylic resin. By grinding one endof the resin-coated electrode to produce a substantially flat planarsurface, a portion of the antimony fragment is exposed for sensingpurposes. Unfortunately, the grinding action tends to pull the exposedantimony portion away from the acrylic resin coating, resulting in theformation of micro-crevices between the exposed antimony portion and theacrylic resin coating. In some cases, fluids may become trapped withinthese micro-crevices, resulting in sample contamination and erroneous pHmeasurements when the electrode is transferred to another position. Inaddition, fluctuations in pH measurements may still occur if the exposedantimony portion does not exhibit a completely smooth sensing surface.

In addition to inconsistent and erratic pH measurements, theabove-mentioned antimony electrodes suffer from several otherdisadvantages. As noted above, conventional antimony electrodes aretypically encased within inflexible materials, such as glass tubes orhard-setting resins. These inflexible materials are not conducive tominimizing patient discomfort when measuring in vivo pH levels. Inaddition, the above-mentioned antimony electrodes require the use ofexternal reference and temperature electrodes; the disadvantages ofwhich will be described in more detail below.

pH-sensitive electrodes, such as the glass and antimony electrodesdescribed above, are configured to provide an electrical potential thatis sensitive to changes in hydrogen ion concentration. However,pH-sensitive electrodes must be combined with reference electrodes,which are configured to provide a constant electrical potentialindependent of hydrogen ion concentration, to determine the pH of asample medium. In this manner, the pH may be determined by the“electrode potential difference,” or the difference in electricalpotentials measured by the pH-sensitive electrode (i.e., the activeelectrode) and the reference electrode.

As noted above, most conventional pH-sensitive electrodes are used incombination with external reference electrodes, which are coupled to thesample medium at a location spaced apart from the active electrode.Examples of conventional external reference electrodes include skinsurface electrodes (e.g., a standard EKG electrode) and separate needleelectrodes, which may be placed in the vicinity of the sample medium orsimply within the patient's body (e.g., within any subcutaneous tissue).As another example, reference half-cells have also been combined withconventional pH-sensitive electrodes. In general, a reference half-cellis an external reference electrode, which is electrochemically coupledto the sample medium via a salt bridge, and typically includes ametal-chloride electrode (e.g., a calomel (Hg:HgCl) or Ag:AgClelectrode) immersed within an electrolyte. Unfortunately, due to theinevitable distance separating the active and reference electrodes, adecrease in accuracy and an increase in time response can be attributedto all external reference electrodes.

Due to the influence of temperature on antimony, pH measurementsobtained with antimony electrodes are often offset, and thus, requiretemperature compensation to obtain “true” pH measurements. Previousattempts at temperature compensation include obtaining and manuallyentering a patient's body temperature into an analytical device.Alternatively, an external temperature electrode may be used to detectthe temperature of an area somewhat removed from the antimony electrode.Unfortunately, such methods are often inconvenient and sometimesinaccurate (e.g., when the measured temperature differs from thetemperature at the pH measurement site).

Therefore, a need exists for a pH-sensitive electrode that overcomes thedisadvantages described above, and more specifically, for a combinationpH probe having an antimony electrode, a reference electrode and atemperature electrode formed within a single probe housing. Such acombination pH probe would provide stable and accurate pH measurements,while demonstrating a time response, which is significantly faster thanthe time response of conventional electrodes. Preferably, thecombination pH probe would provide a minimally invasive means forobtaining quick and accurate pH measurements within in vivo or in vitrosamples of physiological fluids, such as blood plasma, gastricsecretions, pancreatic secretions, saliva, and other bodily fluids.

In addition to physiological fluids, the combination probe would alsoprovide a minimally invasive means for obtaining in vivo pH measurementsof interstitial fluids within physiological tissues and muscles. Asnoted above, conventional electrodes are often used for monitoringchanges in intra-arterial or intra-venous blood plasma pH. Due to thecompensatory effects of buffering in the blood, however, such monitoringprovides an undesirably late indication of underlying problems, whichmanifest originally within the affected tissues and muscles.Unfortunately, detecting a change in the blood plasma pH indicates thatirreversible damage to the tissue cells has already occurred.

Recently, a few electrodes have been described as able to monitor pHlevels within human or animal tissues, muscles and organs. Due to theirrelatively large size, however, these electrodes inevitably cause atleast some amount of local tissue damage. In some cases, insertion of anelectrode greater than 1.0 mm in diameter may inflict enough localtissue damage to cause intracellular release of substantial amounts ofhydrogen ions, resulting in local ischemia and underestimated pHmeasurements.

Clearly, a need remains for a combination pH probe having pH-,reference-, and temperature-sensing capabilities formed within a probehousing, which is small enough for obtaining in vivo pH measurementswithin tissues and muscles without inflicting significant local tissuedamage.

SUMMARY OF THE INVENTION

The problems outlined above may, in large part, be addressed by aminimally invasive, micro-sized pH probe having a pH-sensitiveelectrode, a reference electrode and a temperature electrode arrangedwithin a housing of the probe. As used herein, the term “micro-sized”relates to an outer diameter, which eliminates or otherwise minimizesthe amount of tissue damage caused by insertion of the pH probe intophysiological tissues or muscles. In one example, an outer diameter ofthe probe is between about 0.5 mm and about 1.25 mm. Thoughsubstantially larger diameters are possible, an outer diameter ofapproximately 0.8 mm or less is preferred. As such, the pH probedisclosed herein may be particularly useful for obtaining in vivo pHmeasurements in delicate circumstances (e.g., monitoring myocardialmetabolism during cardiac surgery or monitoring pH levels withinneonates), in addition to circumstances normally encountered within thefield of pH sensing.

In one embodiment, a pH probe for determining a pH level of a samplemedium is disclosed herein. The term “sample medium,” as used herein,may include any acid-base solution or any substance containing anacid-base solution therein. In a particular example, a sample medium mayinclude any physiological medium, such as extracellular fluid (i.e.,interstitial fluid or blood plasma) found within or between connectivetissues, muscles and organs. However, the pH probe is not necessarilylimited to measuring pH within only physiological mediums and may alsobe used in other applications, such as biotechnology and environmentalsciences. As such, the pH probe described herein may also be used formeasuring pH of foods, beverages, chemicals, drugs, natural and publicwater supplies, soil or any other medium normally monitored for pH.

In some cases, the pH probe may include a probe housing consisting of aninner tube concentrically arranged within an outer tube. Preferably, theinner and outer tubes are formed of relatively flexible materials, so asto minimize patient discomfort when obtaining in vivo pH measurements.In some cases, a lumen of the inner tube may include a pH-sensitiveelectrode having a sensing portion, which protrudes from a first end ofthe inner tube for detecting a signal used to determine the pH level ofthe sample medium. In other words, a sensing portion of the pH-sensitiveelectrode may be configured to detect an electrical potential (typicallyin milli-volts), which is responsive to changes in hydrogen ionconcentration of the sample medium.

In a preferred aspect of the present invention, the sensing portion ofthe pH-sensitive electrode includes a smooth hemispherical tip, which isvirtually free of micro-crevices or other blemishes that may otherwisecause undesirable fluctuations in pH measurements. In particular, thepH-sensitive electrode may be an antimony electrode having a sensingportion and a conductive portion. A method of forming the pH-sensitiveelectrode is also disclosed herein and may include forming the sensingportion by dipping one end of an antimony rod, or piece thereof, into amolten solution of antimony and/or antimony oxide. By allowing thesensing portion to harden while pointing in a downward direction, acompletely smooth hemispherical tip is formed due, in part, to surfacetension of the molten antimony.

In some cases, a reference electrode and a temperature electrode may beincluded within a space between the inner tube and the outer tube of thepH probe. The reference electrode may fill at least a portion of thespace, while the temperature electrode may be arranged along one side ofthe space. Alternate arrangements of the reference and temperatureelectrodes within the pH probe are entirely possible and within thescope of the invention.

Regardless of arrangement, the reference electrode may be configured toprovide a constant electrical potential (typically in milli-volts),which is independent of hydrogen ion concentration. In this manner, thepH level of the sample medium may be determined by the “electrodepotential difference” or the difference in electrical potentialsmeasured by the pH-sensitive electrode and the reference electrode.Electrode drift and other noise factors are advantageously reduced to aminimum by positioning the reference electrode within the pH probehousing, and thus, minimizing the distance between the pH-sensitiveelectrode and the reference electrode.

Regardless of arrangement, the temperature electrode may include atemperature sensitive element responsive over a substantially largerange of temperature values (e.g., between about 0° C. and about 100°C.). By positioning the temperature electrode within the pH probehousing, the temperature sensitive element is able to detect a localtemperature of the sample medium with an accuracy greater thanpreviously possible with external temperature electrodes. In thismanner, the pH probe of the present invention advantageously provides amore accurate means for correcting a temperature dependency of theelectrical potential measured by the pH-sensitive electrode.

In a preferred aspect of the present invention, the pH probe includesone or more diffusion windows located within a sidewall of the outertube. In some cases, the one or more diffusion windows may also belocated proximate to a first end of the outer tube (e.g., within a partof the outer tube that is near the sensing portion of the pH-sensitiveelectrode). In general, the diffusion windows are configured to provideelectrical coupling between the reference electrode and the samplemedium. In particular, the diffusion windows allow a controlled amountof electrolytic solution to diffuse into the sample medium, therebyproviding an electrochemical connection between the sample medium andthe reference electrode.

In another embodiment, a system for monitoring a pH level of a samplemedium is disclosed herein as including a pH probe having a pH-sensitiveelectrode, a reference electrode and a temperature electrode arrangedwithin a flexible probe housing, as described above. In this manner, thepH-sensitive electrode may detect a voltage associated with the pH levelof the sample medium, the reference electrode may detect a base voltageof the sample medium, and the temperature electrode may detect atemperature value of the sample medium. In addition, the system mayinclude a processing means, which is coupled to the pH probe andconfigured to determine the pH level of the sample medium using thevoltage, the base voltage and the temperature value.

In yet another embodiment, a method for manufacturing a pH probe isdisclosed herein. In general, the method may include providing a probehousing having an inner tube concentrically arranged within an outertube of the probe housing. In addition, the method may include formingone or more diffusion windows within a sidewall of the outer tubeproximate to a first end of the outer tube. Furthermore, the method mayinclude arranging a plurality of electrodes each having a sensingportion and a conductive portion within the probe housing. Such anarrangement may ensure that a sensing portion of one of the plurality ofelectrodes protrudes from a first end of the probe housing, while aconductive portion of each of the plurality of electrodes protrudes froma second end of the probe housing. Subsequently, the method may includesealing the first and second ends of the probe housing with a sealantmaterial, such that only the protruding portions of the plurality ofelectrodes remain exposed.

In a preferred aspect of the present invention, the method may includeinserting an electrolytic solution into a space bounded by the outertube, the inner tube and the sealant material, such that an entirety ofthe space is filled with the electrolytic solution. A particularadvantage of the current method may be realized by inserting theelectrolytic solution during manufacturing of the probe, as opposed toconventional methods that require the solution to be inserted by anend-user immediately before using the probe. As such, the current methodimproves upon conventional methods by significantly reducing the probepreparation time (i.e., the amount of time needed to prepare the probefor use), as well as reducing the possibility for contamination (e.g.,due to user-mediated loading of the electrolytic solution). The currentmethod may also include sealing the one or more diffusion windows, suchthat evaporation and/or crystallization of the electrolytic solution aresubstantially prevented. In particular, the method may include placing aprotective cap around the first end of the probe housing.

In yet another embodiment, a method for using a pH probe is disclosedherein. Such a method may include removing a protective cap, whichextends around an outer tube of the probe housing to provide a hermeticand hydrophobic seal over the one or more diffusion windows.Subsequently, the method may include inserting the pH probe into asample medium without first having to fill the space between the outertube and the inner tube with an electrolytic solution. As noted above,the current method greatly reduces the probe preparation time and thepossibility of contaminating the pH probe.

BRIEF DESCRIPTION OF THE DRAWINGS

Other objects and advantages of the invention will become apparent uponreading the following detailed description and upon reference to theaccompanying drawings in which:

FIG. 1 is a three-dimensional view showing a top portion of an exemplaryprobe used for determining a pH level of a sample medium;

FIG. 2 is a lateral cross-sectional view of the pH probe of FIG. 1;

FIG. 3 illustrates an exemplary pH monitoring system including alongitudinal cross-sectional view of the pH probe of FIG. 1;

FIG. 4 is a flow-chart diagram illustrating an exemplary method offorming a pH-sensitive electrode included within the pH probe of FIGS.1-3;

FIGS. 5A-C illustrate an exemplary method for manufacturing the pH probeof FIGS. 1-3; and

FIG. 6 is a flow-chart diagram illustrating an exemplary method forusing the pH probe of FIGS. 1-3.

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof are shown by way ofexample in the drawings and will herein be described in detail. Itshould be understood, however, that the drawings and detaileddescription thereto are not intended to limit the invention to theparticular form disclosed, but on the contrary, the intention is tocover all modifications, equivalents and alternatives falling within thespirit and scope of the present invention as defined by the appendedclaims.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Turning to the drawings, exemplary embodiments of a pH probe inaccordance with the present invention are shown in FIGS. 1-3. Inparticular, FIG. 1 illustrates a top portion of pH probe 10, while alower portion of the probe is shown cut away for distinguishing probeelements. In addition, FIGS. 2 and 3 respectively illustrate lateral andlongitudinal cross-sectional views of pH probe 10. Therefore, exemplaryprobe elements and their arrangements within pH probe 10 may bedescribed concurrently in reference to FIGS. 1-3.

As shown in FIGS. 1-3, a probe housing of pH probe 10 includes outertube 20 and inner tube 30. In most cases, inner tube 30 isconcentrically arranged within outer tube 20, however, alternativearrangements are possible and within the scope of the invention. Forexample, inner tube 30 and outer tube 20 may be alternatively arrangedin a side-by-side, or parallel, configuration. However, such aconfiguration is generally not preferred since it does not allow auniform dispersion of electrolytic solution around the tube housing thepH-sensitive electrode. Regardless of arrangement, inner tube 30 andouter tube 20 are preferably formed from sections of substantiallyflexible tubing; examples of which may include polyamide tubing,polyethylene tubing, Teflon™ tubing, or any other flexible tubingapproved for medical use (or at least highly resistant to chemicals andmoisture). Such flexibility may advantageously minimize patientdiscomfort when pH probe 10 is used for obtaining in vivo pHmeasurements. When pH is to be measured within in vitro or non-medicalsamples, however, inner tube 30 and outer tube 20 may alternativelyinclude other materials not approved for medical use (e.g., flexible PVCtubing).

A pH probe in accordance with the present invention is preferably“micro-sized” and, therefore, may be particularly suitable for use indelicate mediums (e.g., cardiac muscle, neonates, small animals, etc.).More specifically, pH probe 10 preferably demonstrates a relativelysmall outer diameter, which allows the probe to be utilized in such amanner. Though a minimum outer diameter of pH probe 10 is generallypreferred, a range of outer diameters between about 0.5 mm and about1.25 mm may be used to describe a “micro-sized” pH probe.

In addition, the probe housing of pH probe 10 is preferably configuredto include a plurality of electrodes, and more specifically, to includepH-sensitive electrode 40, reference electrode 50 (shown in FIGS. 2 and3) and temperature electrode 60. In most cases, pH-sensitive electrode40 is arranged within a lumen of inner tube 30, while referenceelectrode 50 and temperature electrode 60 reside within a space betweeninner tube 30 and outer tube 20. Of course, alternate arrangements ofthe electrodes are possible, especially in cases where the configurationof the probe housing differs from that illustrated in FIGS. 1-3.

In general, pH-sensitive electrode 40 may be formed from any materialsensitive to fluctuations in ion levels within a sample medium.Preferably, pH-sensitive electrode 40 is formed from antimony (Sb);though other materials known for having pH sensing capabilities (e.g.,palladium) may alternatively be used. An exemplary method of forming anantimony pH-sensitive electrode is illustrated in FIG. 4 and describedin more detail below.

In general, reference electrode 50 may include one or moreelectrolytically coupled elements; the combination of which fills atleast a portion of the space between inner tube 30 and outer tube 20. Ina preferred embodiment, reference electrode 50 consists of a pluralityof elements, e.g., porous thread material 52, electrical conductor 54and electrolytic solution 56, which are arranged within the spacebetween the inner and outer tubes. In some cases, porous thread material52 is arranged along one side of the space and extends in a continuousmanner to an opposite side of the space, as shown in FIGS. 1 and 3.Alternatively, porous thread material 52 may be arranged along only theone side, only the opposite side, or may continuously or periodicallyalternate between sides (e.g., by spiraling around a perimeter of innertube 30). Regardless of arrangement, porous thread material 52 may beformed of any fibrous material capable of absorbing electrolyticsolution 56. For example, porous thread material 52 is preferably formedas a cotton wick; however, any other flexible material having absorptioncapabilities (e.g., uncoated dental floss) can alternatively be used.

In some cases, electrical conductor 54 is arranged along the one side ofthe space, as shown in FIGS. 1 and 3. In other cases, however,electrical conductor 54 may be arranged along the opposite side of thespace or may alternate between sides, similar to the arrangement ofporous thread material 52 described above. Electrical conductor 54 mayinclude any metallic conductor; however, the stability of referenceelectrode 50 should be considered when selecting a material compositionfor electrical conductor 54.

More specifically, chemical activity within reference electrode 50 mayintroduce noise within the pH signal by inducing voltage fluctuations inthe absence of electrode input. Fortunately, such noise may be reducedor substantially eliminated with proper choice of materials and/or byspecial treatment of the materials used to form electrical conductor 54.To improve the stability of reference electrode 50, electrical conductor54 preferably contains at least some amount of silver and at least someamount of chloride. For example, electrical conductor 54 may be formedby coating substantially any metallic wire with silver chloride.

In a preferred embodiment, however, electrical conductor 54 is formed bycoating a silver wire with silver chloride to maximize the stability ofreference electrode 50. In some cases, coating may be performedelectrolytically by placing two pieces of silver wire into a saltsolution (e.g., a bromide-free sodium-chloride solution). By connectingthe two pieces to opposite terminals of a voltage source, silver ionsfrom one piece of silver wire diffuse into the solution to combine withchloride ions. Neutral silver chloride molecules produced by thecombination may then electrolytically coat the other piece of silverwire. In other cases, however, coating may be achieved by dipping asilver wire into a molten solution of silver chloride.

In some cases, electrolytic solution 56 fills at least a portion of thespace to provide an electrical connection between porous thread material52 and electrical conductor 54. More specifically, electrolytic solution56 may fill the space bound by inner tube 30, outer tube 20 and sealantmaterials 70 and 80, which as discussed in more detail below, provide ahydrophobic seal at the distal ends of pH probe 10. In general,electrolytic solution 56 may be any nonmetallic conductor in whichelectrical current is carried by the movement of ions. Thus,electrolytic solution 56 may also be referred to as an “electrolyte.”Preferably, electrolytic solution 56 is a viscous fluid, or gel,consisting of one or more chlorides selected from a group comprisingpotassium chloride (KCl), silver chloride (AgCl) and sodium chloride(NaCl). However, electrolytic solution 56 is not limited to only thosechlorides discussed herein, and may alternatively include otherchlorides capable of performing the same function.

In general, temperature electrode 60 may include any appropriately sizeddevice capable of detecting temperatures within an aqueous solution. Asused herein, the term “appropriately sized” refers to an outer diameterof temperature electrode 60, which allows electrode 60 to beincorporated into pH probe 10. As such, the size of temperatureelectrode 60 may be directly dependent on the size of pH probe 10, andvice versa. In most cases, a temperature electrode configured for usewithin the micro-sized pH probe of the present invention will have anouter diameter substantially less than or equal to about 0.5 mm.Preferably, the outer diameter of temperature electrode 60 is less thanor equal to about 0.33 mm. In some cases, temperature electrode 60 maybe responsive within a range of temperatures that occur within aparticular sample medium. It may be preferred, however, that temperatureelectrode 60 be responsive to a substantially large range of temperaturevalues (e.g., about 0° C. to about 100° C.) to avoid limiting the pHprobe to operation within only particular mediums.

Exemplary devices that may qualify as candidates for temperatureelectrode 60 include thermistors, thermocouples and resistancetemperature detectors (RTDs). However, thermistors may be generallypreferred due to the increased circuit complexity associated withthermocouples (i.e., thermocouples typically require a referencejunction) and the relatively higher cost of RTDs. In general,temperature electrode 60 may include any temperature sensitive device,which demonstrates an acceptable trade-off between minimum size andcost, and maximum accuracy.

Furthermore, each of the electrodes within pH probe 10 may be describedas including a “sensing portion” and a “conductive portion.” As shown inFIGS. 1 and 3, for example, a sensing portion of pH-sensitive electrode40 is the portion protruding from a first end of inner tube 30, whilesensing portions of reference electrode 50 and temperature electrode 60remain within the space between inner tube 30 and outer tube 20. On theother hand, conductive portions of each of the electrodes may beindicated by the portions, which extend outward from withincorresponding opposite (i.e., second) ends of inner tube 30 and outertube 20. In this manner, “sensing portions” may be configured fordetecting signals, whereas “conductive portions” may be configured, atleast in part, for transmitting the detected signals to output terminal110 of pH probe 10.

As noted above, a means is provided for sealing the distal ends (i.e.,the first and second ends) of pH probe 10. For example, sealant material70 may be applied (or arranged proximate) to the first ends of innertube 30 and outer tube 20, such that only the sensing portion of pHelectrode 40 protrudes from a surface of sealant material 70. As such,sealant material 70 may include any means by which to provide ahydrophobic seal between the protruding sensing portion and the firstends of the inner and outer tubes. In addition, sealant material 80 maybe applied (or arranged proximate) to the second ends of inner tube 30and outer tube 20, such that only the conductive portions of each of theelectrodes protrude from a surface of sealant material 80. As such,sealant material 80 may include any means by which to provide ahydrophobic seal between the protruding conductive portions and thesecond ends of the inner and outer tubes. In this manner, sealantmaterials 70 and 80 serve to electrically isolate pH-sensitive electrode40 from electrodes 50 and 60, in addition to preventing excess leakageof electrolytic solution 56 into the sample medium. Preferably, sealantmaterials 70 and 80 are comprised of any acrylic, epoxy or ion exchangeresins, which are hydrophobic, robust and substantially non-toxic tohumans or animals.

In a preferred aspect of the present invention, pH probe 10 includes oneor more diffusion windows 90 located within a sidewall of outer tube 20.In general, diffusion windows 90 are located proximate to the first endof outer tube 20 and are configured to provide electrical couplingbetween reference electrode 50 and the sample medium. Diffusion windows90 also provide a means for temperature electrode 60 to detect a localtemperature of the sample medium. In most cases, diffusion windows 90include approximately one to four small “windows” or openings by whichelectrolytic solution 56 may pass unimpeded through the sidewall ofouter tube 20. In this manner, diffusion windows 90 beneficially allow acontrolled amount of electrolytic solution 56 to quickly diffuse intothe sample medium, thereby providing an electrolytic connection betweenthe sample medium and portions of porous thread material 52 arranged inthe vicinity of diffusion windows 90.

Alternatively, diffusion windows 90 may be sealed with a porous plug,such as those conventionally made of cotton or wood. Unfortunately, aporous plug may impede diffusion of electrolytic solution 56, therebyincreasing a time response of the pH probe. As such, diffusion windows90 preferably include a number of unsealed openings having a size andarrangement appropriately chosen to ensure quick diffusion of acontrolled amount of electrolytic solution 56 into the sample medium. Asdescribed herein, a “controlled amount” may be any amount, whichprovides an electrolytic connection between the reference electrode andthe sample medium without contaminating the sample medium with excessivesolution. In one example, pH probe 10 may include two diffusion windowshaving a substantially circular configuration and spaced approximately180° apart. However, the number, shape, size and spatial arrangement ofdiffusion windows 90 may be individually chosen to provide anappropriate amount of electrolytic solution for a given application.

In order to prevent evaporation or crystallization of electrolyticsolution 56, diffusion windows 90 may be sealed with protective cap 100during storage and prior to use of pH probe 10. In general, protectivecap 100 is formed of a pliable plastic material, which extends aroundthe first end of outer tube 20 to provide a hydrophobic and hermeticseal over diffusion windows 90. In some cases, protective cap 100 may beformed as a tubular sheath encompassing only the perimeter of the outertube, as shown in FIG. 5C. In other cases, however, protective cap 100may enclose the exposed sensing portion of the pH-sensitive electrode inaddition to the perimeter of the outer tube, as shown in FIG. 3.

An exemplary system for monitoring a pH level of a sample medium willnow be described in further reference to FIG. 3. System 200 preferablyincludes pH probe 10 having pH electrode 40, reference electrode 50 andtemperature electrode 60 arranged within a flexible probe housing, asdescribed above. In this manner, pH electrode 40 may be configured todetect a voltage associated with the pH level of the sample medium,reference electrode 50 may be configured to detect a base voltage of thesample medium, and temperature electrode 60 may be configured to detecta temperature value of the sample medium.

Also included within system 200, processing means 210 is coupled toreceive the voltage, the base voltage and the temperature value from pHprobe 10. In some cases, processing means 210 and pH probe 10 arecoupled via probe leads 120 and probe output terminal 110, as shown inFIG. 3. However, such coupling is not necessarily limited to theembodiment shown in FIG. 3, and may alternatively include any othermeans by which to provide a “wired” or “wireless” connection betweenprocessing means 210 and pH probe 10. In addition, processing means 210may be configured, in some cases, to determine the pH level of thesample medium using the voltage, the base voltage and the temperaturevalue.

In some cases, processing means 210 may be a standard electricalpotential measuring device (e.g., a voltmeter) or one calibrated to readdirectly in pH (e.g., a pH meter). In a preferred embodiment, however,processing means 210 includes a processor (not shown), display screen220 and one or more user-actuated controls 230. As such, processingmeans 210 may be a hand-held or bench-top device containing electronichardware and/or software appropriately chosen to provide a suitableinterface between the probe data (i.e., the voltage, the base voltageand the temperature value) and the display screen. In this manner, theprobe data and/or the pH level may be displayed on display screen 220.As an alternative or addition to display screen 220, processing means210 may include output port 240 for transmitting an analog or digitalsignal, which may represent the probe data and/or the pH level, to anexternal processing device (e.g., a computer) or an external displaydevice (e.g., a computer monitor). In this manner, the externalprocessing device may alternatively be used to determine the pH level ofthe sample medium.

In addition, processing means 210 may be configured for calibrating thepH-sensitive electrode. Exemplary calibration procedures are describedin more detail below. In general, calibration is often necessary due toslight differences in the construction of individual electrodes andother factors that may influence electrode measurements. For example,processing means 210 may also be configured to correct a temperature-and/or oxygen-dependent offset in the pH measurement, and thus, may beconfigured to provide a more convenient and accurate determination ofpH.

Conventional methods have used monocrystalline antimony to form antimonyelectrodes. However, such methods tend to produce expensive andlabor-intensive electrodes, which if not perfectly formed, suffer fromaccuracy, stability and reproducibility problems. Though pH-sensitiveelectrode 40 may be formed of monocrystalline antimony, in some cases,electrode 40 is preferably formed from ultra-pure antimony (i.e.,99.9999% antimony), which is significantly less expensive and laborintensive than its monocrystalline counterpart. Alternative forms ofantimony not specifically discussed herein may also be used to constructpH-sensitive electrode 40.

As shown in FIG. 4, the preferred method of forming pH sensitiveelectrode 40 may begin by heating the ultra-pure antimony to atemperature high enough to transform the antimony into a molten solution(e.g., the melting temperature of antimony is about 630° C.). The methodcontinues by drawing the molten solution of antimony into a disposabletube, such as a thin glass capillary tube (step 400). An inner diameterof the glass capillary tube may be less than or equal to the innerdiameter of inner tube 30 (e.g., about 0.4 mm to about 1.0 mm). Ingeneral, the molten solution contains at least some amount of antimony.More specifically, the molten solution may contain pure antimony, butmay alternatively comprise a mixture of antimony and antimony oxide. Asa result of the melting process, for example, a portion of the pureantimony may be oxidized to form the mixture of antimony and antimonyoxide.

Next, the molten solution may be cooled slowly within the disposabletube to form a solid antimony rod (step 410). Such slow cooling promoteslarge crystal growth, which in turn, enhances the stability of thepH-sensitive electrode. After cooling, one or more fragments may be cut,broken or otherwise detached from the antimony rod after the rod isremoved from the disposable tube (step 420). In general, a diameter of asingle fragment may be less than or equal the inner diameter of innertube 30, and one or more fragments may be used to make individualpH-sensitive electrodes. Preferably, a single fragment is used toconstruct an electrode of minimum size.

Next, one end of an antimony fragment may be dipped into moltenantimony, or more specifically, into a molten solution of antimony andantimony oxide to form a sensing portion of the pH-sensitive electrode(step 430). By allowing the sensing portion to harden while pointing ina downward direction, a completely smooth hemispherical tip is formeddue, in part, to surface tension of the molten antimony. In this manner,the sensor tip (or sensing portion) of the pH-sensitive electrode maycomprise a very thin layer of antimony having an oxidized outer surface.To complete construction of the pH-sensitive electrode, a conductivewire is attached to an opposite end of the antimony fragment (step 440).Though the conductive wire is preferably solder attached to the antimonyfragment, other means of attachment may alternatively be used. As such,the antimony fragment and conductive wire may form the conductiveportion of the pH-sensitive electrode.

In this manner, the present method overcomes the disadvantages ofprevious methods of forming an antimony electrode. For example, thepresent method provides an antimony electrode having a completely smoothsensing surface, and thus, eliminates or substantially reduces the pHmeasurement fluctuations caused by micro-crevices or other blemishes inthe surface. As such, a pH-sensitive electrode formed in accordance withthe present method demonstrates a significantly greater stability thanconventional pH-sensitive electrodes. In addition, the present methoddemonstrates a reduction in cost and complexity over conventionalelectrodes.

FIGS. 5A-C illustrate a preferred method of manufacturing pH probe 10.As shown in FIG. 5A, the method may begin by providing a probe housing,which as described above, preferably includes an inner tube (30)concentrically arranged within an outer tube (20). Next, one or morediffusion windows (90) may be formed within a sidewall of the outertube. In some cases, the diffusion windows are formed by means ofpuncturing (e.g., with a micro-sized drill bit), melting (e.g., with alaser beam) or drilling (e.g., with a micro-sized drill bit) through thesidewall of the outer tube. In most cases, however, the diffusionwindows are formed prior to arranging the inner tube within the outertube to avoid damaging the inner tube. In any case, approximately one tofour diffusion windows are usually formed proximate to a first end ofthe outer tube (i.e., within a part of the outer tube that is near thesensing portion of pH-sensitive electrode 40).

Subsequently, a plurality of electrodes (40, 50, 60), each having asensing portion and a conductive portion, may be arranged within theprobe housing. In general, one of the plurality of electrodes (40) maybe arranged within the inner tube, while the remaining electrodes (50,60) are arranged within a space between the inner tube and the outertube. In addition, the plurality of electrodes may be arranged such thata sensing portion of one of the plurality electrodes (40) protrudes froma first end of the probe housing, while a conductive portion of each ofthe plurality of electrodes (40, 50, 60) protrudes from a second end ofthe probe housing. More specifically, the pH-sensitive electrode (40)may be positioned within the probe housing so that only a sensingportion of the electrode is allowed direct contact with the samplemedium. Indirect contact between the reference electrode (50), thetemperature electrode (60) and the sample medium is provided via thediffusion windows (90) and the electrolytic solution (56).

Numerous advantages arise from arranging the plurality of electrodeswithin the probe housing. By positioning the pH-sensitive electrodewithin the inner tube, for example, the pH-sensitive electrode may beelectrically isolated from the electrodes positioned within the outertube. In addition, positioning the reference electrode within the probehousing minimizes the distance between the pH-sensitive electrode andthe reference electrode. Such an arrangement advantageously reduces atime response of the probe, while minimizing electrode drift and othernoise factors normally associated with external reference electrodes.Furthermore, positioning the temperature electrode within the probehousing allows the temperature electrode to detect a local temperatureof the sample medium, as opposed to a general temperature detected by anexternal temperature electrode. Thus, the internal temperature electrodedescribed herein may provide a greater accuracy than possible withexternal temperature electrodes. Consequently, the arrangement disclosedherein provides a pH probe, which responds faster and with greateraccuracy and stability than previously possible.

Next, the method includes sealing the first and second ends of the probehousing with a sealant material (70, 80), as shown in FIG. 5B. Inparticular, the first and second ends of the probe housing are sealed,such that only the protruding portions (500, 510) of the plurality ofelectrodes remain exposed. More specifically, any space between theprotruding portions and the ends of the probe housing is filled entirelywith sealant material to avoid contamination of the sample medium and/orcontamination within the probe. In this manner, the sealant materialprevents excess leakage of the electrolytic solution (56) into thesample medium, and also prevents fluids from the sample medium fromentering the probe (which, as described above, may cause erratic pHmeasurements). In addition, the sealant material may furtherelectrically isolate the pH-sensitive electrode from the remainingelectrodes within the probe housing.

In a subsequent step of the method, the electrolytic solution (56) maybe inserted into a space bounded by the outer tube, the inner tube andthe sealant material, as shown in FIG. 5C. More specifically, the entirespace is filled with electrolytic solution to avoid air bubbles orincomplete filling, which may otherwise cause pH measurements to beerratic. In some cases, a vacuum may be created within the space beforeinserting the electrolytic solution to ensure complete filling of thespace. The vacuum, as well as the insertion of electrolytic solution, isachieved via the one or more diffusion windows. Alternatively, theelectrolytic solution may be forcefully inserted through the diffusionwindows to completely fill the space. In such a case, it may benecessary to form a small hole within the outer tube to allow air withinthe space to escape; the small hole may be subsequently filled with asealant material.

In a preferred aspect of the present invention, the electrolyticsolution is inserted during a manufacturing step of the probe, asopposed to packaging the probe dry and relying on a user to insert thesolution. By doing so, the present method significantly reduces theprobe preparation time (i.e., the time needed to prepare the probe foruse), and eliminates the possibility of contamination due touser-mediated loading of the probe. Since the pH probe may be stored fora period of time, the diffusion windows are sealed with a protective cap(100) to prevent evaporation or crystallization of the electrolyticsolution.

FIG. 6 illustrates a preferred method of using pH probe 10. In somecases, the method may begin by removing the protective cap overlying theone or more diffusion windows (step 600). After removing the protectivecap, the pH probe may be calibrated using one or more standard buffersolutions (step 610). In some cases, the pH probe may be calibrated byplacing the exposed sensing portion of the pH-sensitive electrode intoat least one buffer solution having a pH level similar to an expected pHlevel of the sample medium. Though previous investigators have reporteda non-linear response for antimony electrodes over the entire pH scale,others indicate that the response may be substantially linear within atleast the calibration range (e.g., about 6.8 to about 7.5 if using 6.84and 7.45 calibrated buffer solutions). Therefore, it may be beneficialto calibrate the pH probe using a buffer solution having a pH levelsimilar to an expected pH level, especially when obtaining pHmeasurements within physiological mediums.

In addition, antimony electrodes are often affected by temperature andoxygen tension within the sample medium. For example, false pHmeasurements may occur when a sample temperature differs from thetemperature at which a pH probe is calibrated. In particular, highersample temperatures may cause pH measurements to appear higher (i.e.,over exaggerate the degree of alkalosis), while lower sampletemperatures may cause pH measurements to appear lower (i.e., overexaggerate the degree of acidosis) than the actual pH of the samplemedium. Therefore, it may be beneficial, in some cases, to calibrate thepH probe using a buffer solution having a temperature similar to atemperature of the sample medium. Alternatively, or in addition to,temperature compensation may be performed to eliminate anytemperature-dependent offset in the pH measurement.

In the same manner, false pH measurements may occur if oxygen levelsdiffer between the sample medium and the buffer solution used forcalibration. Contrary to the effect of temperature, however, higheroxygen levels in the sample medium cause pH measurements to appearlower, while lower oxygen levels in the sample medium cause pHmeasurements to appear higher than the actual pH of the sample medium.Therefore, it may also be beneficial to calibrate the pH probe using abuffer solution having an oxygen level similar to that of the samplemedium. In some cases, remaining oxygen-dependent offsets may becompensated for analytically.

In a preferred embodiment, the pH probe is generally calibrated usingtwo or more calibrated buffer solutions and a neutral solution, such asdistilled or de-ionized water. After connecting the pH probe to theprobe meter (e.g., processing means 210 of FIG. 3) and removing theprotective cap, the tip of the pH probe is immersed within the neutralsolution until the pH probe becomes stable (e.g., 30 seconds, or untilthe pH probe reaches an equilibrium state). The pH probe may be removedfrom the neutral solution and quickly dried before immersing the tip ofthe pH probe into a calibrated buffer solution having a substantiallyacidic pH (e.g., a solution having a pH less than 7.0). In one example,the acidic calibrated buffer solution may have a pH of about 6.84. Oncethe pH probe is stable (e.g., after 15 seconds of immersion), a pH ofthe acidic solution is measured and the probe is removed. Once again,the pH probe may be dried, and the above steps may be repeated for acalibrated buffer solution having a substantially alkaline pH (e.g., asolution having a pH greater than 7.0). In one example, the alkalinecalibrated buffer solution may have a pH of about 7.45. In some cases,the probe may be ready for use after drying the probe once more.Alternatively, the above steps may be repeated as necessary.

After calibration, the pH probe may be inserted into the sample medium(step 620) for monitoring the pH level of the sample medium (step 630).As noted above, the probe housing is constructed of flexible tubing, soas to minimize patient discomfort when obtaining in vivo pHmeasurements. Due to the flexibility of the housing, however, it may benecessary to insert the pH probe through a small needle introducer, orrigid tube used for puncturing an outer surface of the sample medium. Inmost cases, 18-, 19- or 20-gauge introducers (i.e., about 1.24 mm, 1.07mm and 0.89 mm in diameter, respectively) may accommodate themicro-sized pH probe of the present invention. In some cases, however,introducers of different sizes may be appropriate, whereas, in othercases, an introducer may not be required to insert the pH probe.

In general, the micro-sized pH probed described herein may be used formonitoring or measuring pH within any acid-base solution or substancecontaining an acid base solution. For example, the pH probe may be usedto measure pH in the fluids of calibrated buffer solutions or othermedia, such as meats, fruits, vegetables, and other food and beverageproducts. The pH probe may also be used to measure the pH of certaindrugs and chemicals to ensure uniformity during processing. In apreferred embodiment, the pH probe is used for measuring the pH ofphysiological fluids. For example, the pH probe may be used in dentistryfor measuring pH in dental plaque and oral secretions, or in medicinefor measuring pH in blood plasma, gastric secretions and pancreaticsecretions.

However, a pH probe in accordance with the present invention isparticularly suitable for monitoring or measuring pH of extracellularfluids within human or animal tissues and muscles. In particular, the pHprobe described herein is both micro-sized and minimally invasive, andtherefore, may be used for obtaining in vivo pH measurements withintissues and muscles without inflicting significant local tissue damage(e.g., due to having a diameter substantially less than 1.0 mm). Assuch, the pH probe can be used to provide an earlier indication ofacidosis or alkalosis by measuring pH within the affected tissues ormuscles, as opposed to measuring the pH of blood plasma (which providesa relatively late indication). For example, the pH probe may provide anearly indication of inadequate oxygen perfusion within the affectedtissues or muscles. The pH probe may be especially suitable for use indelicate circumstances (e.g., monitoring cardiac muscle, neonates, smallanimals, etc.) due to the minimum amount of trauma inflicted byinsertion of the pH probe within the sample medium or the patient.

In addition, the micro-sized pH probe may be useful for continual pHmonitoring within human or animal tissue, muscle, organs or blood. Forexample, the micro-sized pH probed may be used for monitoring pH inneonates, critical care patients (e.g., patients in shock orexperiencing a heart attack), patients with blood disorders, duringsurgical procedures and numerous other clinical applications. Inparticular, the pH probe may be used for directly monitoring a clinicalsituation of a patient undergoing cardiac surgery, which as describedabove, was previously infeasible due to conventional electrodes beingsubstantially greater than 1.0 mm in diameter. In addition, the pH probemay be used for monitoring neonatal sepsis (i.e., a blood bacterialinfection plaguing infants less than four weeks of age). Currently,neonatal sepsis is monitored by measuring the infant's body temperature,which is an indication of the presence of infection.

It will be appreciated to those skilled in the art having the benefit ofthis disclosure that this invention is believed to provide a minimallyinvasive, micro-sized pH probe having a pH-sensitive electrode, areference electrode and a temperature electrode arranged therein.Further modifications and alternative embodiments of various aspects ofthe invention will be apparent to those skilled in the art in view ofthis description. It is intended that the following claims beinterpreted to embrace all such modifications and changes and,accordingly, the specification and drawings are to be regarded in anillustrative rather than a restrictive sense.

What is claimed is:
 1. A method of forming a pH-sensitive electrode, themethod comprising: drawing a molten solution comprising some amount ofantimony into a disposable tube; cooling the molten solution to form anantimony rod; detaching a fragment of the antimony rod after removingthe antimony rod from the disposable tube; forming a sensing portion ofthe pH-sensitive electrode by dipping one end of the fragment into themolten solution and allowing the sensing portion to harden while thepH-sensitive electrode is secured in a downward-pointing direction,wherein said forming creates a sensing portion having a substantiallysmooth hemispherical configuration adapted to maximize a stability ofthe pH-sensitive electrode.
 2. The method as recited in claim 1, whereinprior to the step of drawing, the method further comprises heating theantimony to a temperature high enough to transform the antimony into themolten solution.
 3. The method as recited in claim 1, wherein the moltensolution comprises pure antimony.
 4. The method as recited in claim 1,wherein the molten solution comprises a mixture of antimony and antimonyoxide.
 5. The method as recited in claim 1, wherein a diameter of thefragment is less than about 1.0 mm.
 6. The method as recited in claim 1,wherein a diameter of the fragment is within a range of about 0.4 mm toabout 0.8 mm.
 7. The method as recited in claim 1, further comprisingforming a conductive portion of the pH-sensitive electrode by attachinga conductive wire to an opposite end of the fragment.